Aim: This study aims at testing registered nurses’ knowledge while working at mental health facilities and general care hospitals, through an exploratory non-experimental study using a random sample of nurse population across Saudi health facilities. Materials and Methods: The study participants were asked to complete a questionnaire consisting of four sections. Section 1 consisted of 21 questions, requesting participants to provide their background and demographic information, followed by a delirium-knowledge-assessment questionnaire Section 2 consisting of 15 questions of which eight of them required true-false answers, and the remaining questions were multiple-choice. In Section 3, the research tool was a dementia-knowledge-assessment survey consisted of 27 questions that required true-false answers to a given statement about dementia. In Section 4, the depression-knowledge assessment survey provided multiple-choice answers. A total of 265 registered staff nurses SNs were included in the study, and were chosen from three Saudi healthcare centers, with an age range of 24 - 57 years. The participants consisted of 73% females and 27% males. Results: The knowledge of delirium, among the sampled nurses, was not high M = 6.8906, SD = 2.13363. The employing health center influenced the delirium knowledge significantly, in addition to the job title of the participant, and their highest level of education, in addition to the fact of whether the participant has an immediate family member who has ever been diagnosed with any of the 3Ds. The averages significantly differed across the study sample with immediate family members who have been diagnosed with any of the 3Ds and those without ANOVA, p = 0.019. Similar to the delirium knowledge, dementia knowledge, among the study participants, was not high M = 69.2576, SD = 11.29327, and was significantly influenced by the health center, each participant’s gender, nationality, job title, highest level of education, and the country where they had completed their highest level of education. The scores, obtained for dementia knowledge, were positively and significantly correlated to how individual participants rated their current dementia knowledge ANOVA, p < 0.001. Besides, the regression analysis, which showed how the participants rated their current dementia knowledge, confirmed the significance of explaining such a knowledge ANOVA, p < 0.001. Contrary to the delirium and dementia knowledge, the participants’ depression knowledge was found to be high ANOVA, SD = 1.97367, and was significantly influenced by the employing health center, the participant’s gender, nationality, job title, highest level of education, and the country where they had completed their highest level of education. However, the average scores of the measurement of depression knowledge were found to be significantly different among participants from different mental health centers ANOVA, p < 0.001, their genders ANOVA, p < 0.001, and nationalities ANOVA, p < 0.001. Moreover, the average scores obtained from measuring depression knowledge differed significantly across participants holding different job titles ANOVA, p < 0.001, levels of education ANOVA, p < 0.001 and those who completed their highest level of education overseas ANOVA, p < 0.001. Conclusion: Saudi registered nurses’ knowledge of dementia and delirium was found to be limited compared to their knowledge of depression.